ABSTRACT Ixodes scapularis, commonly known as the deer tick, is the predominant tick vector of several human pathogens including Borrelia burgdorferi, the Lyme disease agent and transmits the harbored pathogens to the host during feeding. Vaccines against these tick-borne pathogens are not available. Thisproposalwillexamineanewparadigmthatsuggestsacriticalroleforticksalivaryglycans in provoking immune responses in the host critical to thwart tick feeding. This study will set the tone for the development of tick salivary glycan-based vaccines to block tick feeding and prevent transmissionofmultipletick-transmittedpathogenstothehost. William Trager?s seminal observation showed that repeated tick infestations of non-permissive hostssuchasguineapigsandrabbitsprovokeabriskhumoralimmuneresponsedirectedagainstcritical tick salivary components that results in thwarting tick feeding ? a phenomenon referred to as acquired tick-resistance.Ourinitialobservationsdemonstratethatglycosylationsonsecretedticksalivaryproteins play a significant role in eliciting tick-resistance in guinea pigs. Glycans or carbohydrates decorations present on several tick salivary proteins likely maintain the structure and function of the protein. These glycan decorations potentially serve as ?vector-associated-molecular patterns? (VAMPs) and elicit glycan-specificimmuneresponsesthatresultintickrejection.Todevelopthisconceptandtodetermine theroleofticksalivaryglycansinthecontextoftick-hostinteractionswewill: A.Identifyimmunogenicsalivaryglycanstargetedbytick-resistantguineapigsera. B.Identifysalivaryglycoproteinsthatcontainimmunogenicglycans. C. Determine if immunization of guinea pigs with the glycans or glycoproteins might provoke tick- resistance and consequently thwart tick feeding and prevent pathogen transmission. We will use B. burgdorferiasanexampleofatick-transmittedpathogen. Theresultsofthiseffortwillilluminateanewfacetofticksalivaryproteins?theglycansthat decoratetheproteinsandtheroleoftheseglycansinmodulatinghostimmunityandoffernew approachestoimpairtickfeedingandpreventpathogentransmission.